Preparation of 5-benzyloxyindoleacetonitriles



United States Patent?) PREPARATION OF S-BENZYLOXYINDOLE- ACETONITRILES 6Claims. (Cl. 260--319) The present invention relates to novel organiccompounds, and is more particularly concerned with a novel method forthe production of -benzyloxy-3-indoleacetonitriles and with the productsthus produced.

The compounds of the present invention may be represented by theformula:

HO HTCEN wherein X represents phenyl and wherein Y represents alkyl,cycloalkyl, phenyl, or hydrogen. Within the scope of the term phenyl areincluded substituted phenyl radicals, e. g., alkylphenyl,cycloalkylphenyl, alkoxyphenyl, halophenyl, and aralkylphenyl.

An object of the present invention is to provide new andusefulcompounds, the 5-benzyloxy-3-indoleacetonitriles. An additionalobject is the provision of a novel process for the preparation of thenew compounds. Other objects of the invention will be apparent to thoseskilled in the art to which the invention pertains.

The novel compounds of the present invention are important intermediatesin the preparation of serotonin [1. Biol. Chem. 180, 961 (1949)], apowerful vasoconstrictor. For example, the novel5-benzyloxyindoleacetonitriles may be reduced to S-benzyloxytryptamines,as more fully disclosed in U. S. Patent 2,703,325, and the resultingS-benzyloxytryptamines converted to the desired serotonin, as more fullydisclosed in my co-pending application Serial Number 289,872, filed May24, 1952. These compounds are also useful in the preparation of resinsand polymers, according to the usual procedures for the preparation ofsuch resins or polymers from nitriles and other reactive resiningredients, and in addition are possessive of certain pharmacologicalactivity per se.

According to the method of the present invention, the5-benzyloxy-3-indoleacetonitriles are prepared by the treatment of aS-benzyloxyindole with a Grignard reagent whereby the S-benzyloxyindoleis itself converted into a Grignard reagent. The resulting Grignardreagent is then treated with a haloacetonitrile and thus converted to a5-benzyloxy-3-indoleacetonitrile.

The compounds which are used as starting materials for the method of thepresent invention are the S-benzyloxyindoles. These compounds areprepared by condensing 2-nitro-S-benzyloxytoluenes with ethyl oxalate inthe pres ence of potassium ethoxide to produceZ-nitro-S-benzyloxy-phenylpyruvic acids and reducing the latter withferrous hydroxide to produce 5-benzyloxyind0le-Z-carboxylic acids, whichare then decarboxylated to S-benzyloxyindoles by heating in glycerol,according to the method of Burton and Stoves U. Chem. Soc. (London)1937, 1726].

In this manner numerous S-benzyloxyindoles, includingS-alkylbenzyloxyindoles, 5-cycloalkylbenzyloxyindoles, 5-halobenzyloxyindoles, S-alkoxybenzyloxyindoles,S-aralkylbenzyloxyindoles, S-benzhydryloxyindole, 5-(alpha-al-'kylbenzyloxy)-indoles, 5-(alpha-cycloalkylbenzyloxy)-indoles,5-(parahalobenzhydryloxy)-indoles, 5-(para,para'-dihalobenzhydryloxy)-indo1es, 5-(alpha-alkylalkylbenzyloxy) -indo1es,5-alpha-cycloalkylhalobenzyloxy)-indoles, and the like, are preparedusing 2-nitro-5-alkylbenzyloxytoluenes, e. g.,2-nitro-5-methylbenzyloxytoluenes, 2-nitro-5-cycloalky1benzyloxytoluenes, e. g.,Z-nitro-S-cyclohexylbenzyloxytoluenes, Z-nitro-5-halobenzyloxytoluenes,e. g., 2-nitro 5 chlorobenzyloxytoluenes,2-nitro-5-alkoxybenzyloxytoluenes, e. g.,2-nitro-5-methoxybenzyloxytoluenes, 2-nitro-5-aralkylbenzyloxytoluenes,e. g., 2-nitro-5-benzylbenzyloxytoluenes,2-nitro-S-benzhydryloxytoluene, 2-nitro-S-(alpha-alkylbenzyloxy)-toluenes, e. g., 2-nitro-5- (alpha-methylbenzyloxy) -toluene,Z-nitro-S-(alpha-cycloaikylbenzyloxy)-toluenes, e. g.,2-nitro-5-(alpha-cyclohexylbenzyloxy) -toluene, 2-nitro-5-(halobenzhydryloxy) toluenes, e. g., 2-nitro-5-(para-chlorobenzhydryloxy)-to1uene,Z-nitro-S-(dihalobenzhydryloxy)-to1uenes, e. g., 2- nitro 5(para,para-dichlorobenzhydryloxy) -toluene, 2-nitro-S-(alpha-alkylalkylbenzyloxy) -toluenes, e. g.,2-nitro-5-(alpha-propylpara-methylbenzyloxy) toluenes, and 2 nitro 5(alpha-cycloalkylhalobenzyloxy) toluenes, e. g.,2-nitro-5-(alpha-cyclopentyl-para-bromobenzyloxy)- toluene,respectively, in place of the 2-nitro-5-benzyloxytoluene which is usedto prepare S-benzyloxyindole. Other methods of preparing the startingmaterials of the present invention are known in the art and may be usedif desired. An alternative method is given in my co-pending application,Serial Number 273,149, filed February 23, 1952.

The preparation of the S-benzyloxy-3-indoleacetonitriles is accomplishedby reacting a S-benzyloxyindole with a Grignard reagent and thereafterreacting the resulting S-benzyloxyindolemagnesium halide with ahaloacetonitrile to produce the desired5-benzyloxy-3-indoleacetonitrile. For the Grignard step a great manyGrignard reagents are satisfactory, among them being those prepared fromalkyl halides, cycloalkyl halides, aryl halides, and aralkyl halides,the lower-alkyl halides, such as methyl iodide and ethyl bromide, beingpreferred. The Grignard reaction is carried out in the presence of anorganic solvent, diethyl ether and tetrahydrofuran being preferred,although other organic solvents, suitable for use in Grignard reactions,such as benzene, toluene, or anisole, can also be employed. Thepreparation of the S-benzyloxyindole Grignard reagent is usuallyconducted at the boiling point of the solvent employed, although othertemperatures between about Zero and 150 degrees centigrade, preferablybetween about zero and 100 degrees centigrade, may also be used, alonger reaction period being required in the lower temperature ranges.The resulting S-benzyloxindolemagnesium halide is then reacted with ahaloacetonitrile, such as chloroacetonitrile, bromoacetonitrile,

or iodoacetonitrile, with chloroacetonitrile being preferred. The sameorganic solvent as employed for the previous step is usually utilized,although others may be used if desired. The temperature range for thereaction of the haloacetonitrile and the 5-benzyloxyindolemagnesiumhalide is usually between about zero and degrees Centigrade, with thereaction ordinarily being conducted at the boiling point of the solventemployed. After refluxing for a period of about one to five hours, theresulting 5-benzyloxy-3-indoleacetonitrile is separated by conventionalprocedure, which, for example, may involve a mild hydrolysis, as withdilute acetic acid, to form an ether layer containing the5-benzyloXy-3-indoleacetonitrile and a water layer, from which theether-S-benzyloxy- 3-indoleacetonitrile layer may be separated and driedto give an ethereal solution of the 5-benzyloxy-3-indoleacetonitrile.From this solution, the desired 5-benzyloXy-3- indoleacetonitrile may beobtained in high purity by evaporation or solvent removal according toother conventional procedure.

The following examples will serve to illustrate the process and productsof this invention, but the said invention is not to be considered aslimited thereto.

Example 1.5-ber1z)[wry-3-ind0leacet0nitrile To a Grignard reagentprepared from 4.25 grams (0.03 mole) of methyl iodide and 2.6 grams ofmagnesium in 200 milliliters of ether was added a solution of 5.5 grams(0.025 mole) of S-benzyloxyindole in 200 milliters of ether. Afterheating under reflux for thirty minutes, the mixture was cooled in anice-bath and a solution of three grams (0.04 mole) of freshly-distilledchloroacetonitrile in 100 milliliters of ether was added thereto. Themixture was heated vigorously under reflux for two and one-half hours,cooled and hydrolyzed by the addition of a solution of ten millilitersof glacial acetic acid and ninety milliliters of water. The ether layerwas separated and the aqueous layer extracted with several portions ofether. The combined ether solutions were washed successively with water,

sodium carbonate solution and water, and dried over potassium carbonatefor at least 24 hours to give an ethereal solution of5-benzylox.y3-indoleacetonitrile from which the desired5-benyloxy-3-indoleacetonitrile is obtained by evaporation or otherconventional procedure.

Example 2.5- (para-methylbenzyloxy -3- indoleacetonitrile Example3.5-(pura-benzylbenzyloxy)- S-imioleacetonitrile In essentially the samemanner as disclosed in Example 1,5-(para-benzylbenzyioxy)-3-indoleacetonitrile is prcpared by reactingmethyl iodide Grignard reagent with 5-(para-henzylbenzyloxy)-indole, andthereafter reacting the 5-(para-benzylbenzyloxy)-indolemagnesium iodidewith chloroacctonitrile.

In the same manner other 5-aralkylbenzyloxyindoleaeetonitriles areprepared from the appropriate S-aralkylbenzyloxyindolc, e. g.,5-(para-phenethylbenzyloxy)-3-indoleacetonitrile, 5-meta-phcnylpropylbenzyloxy) -3 -indoleacetcnitrile,5'(para-phenylhexylbenzyloxy)-3-indoleacetonitrile, and the like.

Example 4.5-(para-n'zetlzoxybenzyloxy 3-indoleacetonitrile Inessentially the same-manner as disclosed in Example 1,S-para-methoxybenzyloxy)-3-indoleacetonitrile is prepared byreacting'rnethyl iodide Grignard reagent with5-(para-methoxybenzyioxy)-ind0le, and thereafter react ing theS-(para-methoxybenzyloxy)-indolemagnesiurn iodide withchloroacetonitrile.

In the same manner other 5-alkoxyhenzyloxyindoleacetonitriles areprepared from the appropriate 5-alkoxybenzyloxyindole, such as5-(ortho-ethoxybenzyloxy)-3-indoleacetonitrile, 5(para-propoxybenzyloxy) 3 indoleacetonitrile, 5(nieta-isopropoxybenzyloxy)-3-indoleacetonitrile,5-(para-bntoxybenzyloxy)-3-indoleacetonitrile, 5-(para-amyloxybenzyloxy) -3 -indoleacetonitrile, 5-(metahexoxybenzyloxy)-3-indoleacetonitrile, 5-(para-heptoxybenzyloxy) 3indoleacetonitrile, 5 (para-octoxybenzyloxy)-3-indoleacetonitrile, andthe like.

Example 5 .5-benzhyllry l0xy-3-ind0leace tonitrile In essentially thesame manner as disclosed in Example 1,S-benzhydryloxy-3-indoleacetonitrile is prepared by reacting methyliodide Grignard reagent with S-benzhydryloxyindole, and thereafterreacting the S-benzhydryloxyindole-magnesium iodide withchloroacetonitrile.

In essentially the same manner as disclosed in Example 5, the followingS-halobenzhydryloxy-3-indoleacetonitriles are prepared from theappropriate S-halobenzhydryloxyindoles: 5 (para-iodobenzhydryloxy- 3indoleacetonitrile, 5 (meta-bromobenzhydryloxy) -3 -indoleacetonitri le,5 (para,para dichlorobenzhydryloxy) 3 indoleacetonitrile, and the like.

Example 6 .-5 para-cyclohexylbenzyloxy 3 -indoleacet0nitriie Inessentially the same manner as disclosed in Example 1,5-(para-cyclohexylbenzyloxy)-3-indoleacetonitrile is prepared byreacting ethyl bromide Grignard reagent with5-(para-cyclohexylbenzyloxy) -indole, and thereafter reacting the5-(para-cyclohexylbenzyloxy)-indolernagnesium bromide withbromoacetonitrile.

In the same manner the following are prepared from the appropriate5-cycloalkylbenzyloxyindole:S-(metacyclopentylbenzyloxy)-3-indoleacetonitrile,S-(ortho-cyclopentylbenzyloxy)-3-indoleacetonitrile, 5-(para-cyclopentylbenzyloxy) -3-indoleacetonitrile, 5- ortho-cyclopen tyl'oenzyloxy) 3indoleacetonitrile, 5 (ortho cycloheXyl'oenzyl0Xy)-3-indoleacetonitrile,S-(meta-cyclohexylbenzyloxy) 3-indoleacetonitrile, and the like.

Example 7.5-(para-chlorobenzyloxy)- S-indoleacetonitrile In essentiallythe same manner as disclosed in Example 1,S-(para-chlorobenzyloxy)-3-indoleacetonitrile is prepared by reactingmethyl iodide Grignard reagent with S-(para-chlorobenzyloxy)-indole, andthereafter reacting the S-(para-chlorobenzyloxy)-indolemagnesiuin iodidewith iodoacetonitrile.

In the same manner the following are prepared from the appropriateS-halobenzyloxyindole: S-(meta-bromobenzyloxy) -3-indoleacetonitrile,S-(para-iodobenzyloxy) 3-indoleacetonitrile, 5- (para-fiuorobenzyloxy)-3-indoleacetonitrile, and the like.

Example 8.5-(alpha-methyl-benzyloxy -3-ind0leacetonitrile Inessentiallythe same manner disclosed in Exam- 3 ple l,5-(alpha-methyl-benzyloxy)-3-indoleacetonitrile is prepared by reactingmethyl iodide Grignard reagent with 5-(alpha-methyl-benzyloxy)-indole,and thereafter reacting the 5(alpha-methyl-benzyloxy)-indolemagnesiumiodide with chloroacetonitrile.

In the same manner the following are prepared from the appropriate5-(alpha-alkyl-benzyloxy)-indole: 5- (alpha ethyl benzyloxy) 3indoleacetonitrile, 5 (alpha propyl benzyloxy) 3 indoleacetonitrile, 5(alpha isopropyl benzyloxy) 3 indoleacetonitrile,

5 (alpha octyl benzyloxy) 3 indoleacctonitrile,

and the like.

Example 9.-5- alpha-cyclohexy l-benzyloxy) -3-indoleacetonitrile Inessentially the same manner as disclosed in Example l,5-(alpha-cyclohexyl-benzyloxy)-3-indoleacetonitrile is prepared byreacting methyl iodide Grignard reagent with 5(alpha-cyclohexyl-benzyloxy)-indole, and thereafter reacting the5-(alpha-cycloheXyl-benzyloxy)- indolemagnesium iodide withchloroacetonitrile.

In the same manner the following are prepared from the appropriate5-(alpha-cycloalkyl-benzyloxy)-indole: 5 (alpha cyclobutyl benzyloxy) 3indoleacetonitrile, 5 (alpha cyclopentyl benzyloxy) 3indoleacetonitrile, and the like.

Other representative S-benzyloxy-B-indoleacetouitriles which may beprepared in this manner are: 5 (alpha alkyl alkylbenzyloxy) 3indoleacetonitriles, e. g., 5 (alpha methyl para methylbenzyloxy) 3 indoleacetonitrile, 5 (dicycloalkylbenzhydryloxy) 3 indoleacetonitriles,e. g., 5 (para,para dicyclopentyl benzhydryloxy) 3 indoleacetonitrile, 5(dialkyl benzhydryloxy) 3 indoleacetonitriles, e. g., 5 (para paradimethylbenzhydryloxy) 3 indoleacetonitrile, 5 (dialkoxybenzhydryloxy) 3indoleacetonitriles, e. g., 5 (para,para' dimethoxybenzhydryloxy) 3indoleacetonitrile, 5 (diaralkylbenzhydryloxy) 3 indoleacetonitriles, e.g., 5 (para,para' dibenzyl benzhydryloxy)-3-indoleacetonitrile, and thelike.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art, and the invention is therefore to be limited only by the scopeof the appended claims.

6 I claim: 1. A S-benzylOxy 3 indoleacetonitrile represented by theformula:

CHr-CEN wherein X is selected from the group consisting of phenyl,alkylphenyl, cycloalkylphenyl, alkoxyphenyl, halophenyl, andaralkylphenyl, and Y is selected from the group consisting of phenyl,alkylphenyl, cycloalkylphenyl, alkoxyphenyl, halophenyl, aralkylphenyl,alkyl, cycloalkyl, and hydrogen.

2. S-(para-methylbenzyloxy)-3-indoleacetonitrile.

3. S-(para-benzylbenzyloxy) -3-indoleacetonitrile.

4. 5-(para-methoxybenzyloxy) -3-indoleacetonitrile.

5. 5-benzhydryloxy-3-indoleacetonitrile.

6. 5-benzyloxy-3-indoleacetonit1ile.

References Cited in the file of this patent Wieland et al.: Annalen derChemie, Band 513, pp. 1-25 (1934).

Burton et al.: J. Chem. Soc., 1937, pp. 1726-28.

1. A 5-BENZYLOXY - 3 - INDOLEACETONITRILE REPRESENTED BY THE FORMULA: